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Novel benzimidazole phosphonates as potential inhibitors of protein prenylation |
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| Authors: | Nazmul H Bhuiyan Michelle L Varney David F Wiemer Sarah A Holstein |
| Institution: | 1. Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA;2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;3. Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA;4. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA |
| Abstract: | Benzimidazole carboxyphosphonates and bisphosphonates have been prepared and evaluated for their activity as inhibitors of protein prenylation or isoprenoid biosynthesis. The nature of the phosphonate head group was found to dictate enzyme specificity. The lead carboxyphosphonate inhibits geranylgeranyl transferase II while its corresponding bisphosphonate analogue potently inhibits farnesyl diphosphate synthase. The most active inhibitors effectively disrupted protein prenylation in human multiple myeloma cells. |
| Keywords: | Corresponding author Benzimidazole Farnesyl diphosphate synthase Geranylgeranyl transferase II Inhibition Isoprenoid biosynthesis Carboxyphosphonate Bisphosphonate |
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